Abstract
Original language | English |
---|---|
Article number | 8077 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2023 |
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In: Nature communications, Vol. 14, No. 1, 8077, 01.12.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
AU - Wang, Sheng
AU - Wang, Belinda
AU - Drury, Vanessa
AU - Drake, Sam
AU - Sun, Nawei
AU - Alkhairo, Hasan
AU - Arbelaez, Juan
AU - Duhn, Clif
AU - Bromberg, Yana
AU - Brown, Lawrence W.
AU - Cao, Xiaolong
AU - Cheon, Keun-Ah
AU - Cheong, Kyungun
AU - Choi, Hannyung
AU - Coffey, Barbara J.
AU - Deng, Li
AU - Fremer, Carolin
AU - Garcia-Delgar, Blanca
AU - Gilbert, Donald L.
AU - Glover, Danea
AU - Grice, Dorothy E.
AU - Hagstrøm, Julie
AU - Hedderly, Tammy
AU - Heyman, Isobel
AU - Hong, Hyun Ju
AU - Huyser, Chaim
AU - Kim, Heejoo
AU - Kim, Young Key
AU - Kim, Eunjoo
AU - Kim, Young-Shin
AU - King, Robert A.
AU - Koh, Yun-Joo
AU - Kook, Sodahm
AU - Kuperman, Samuel
AU - Lee, Junghan
AU - Leventhal, Bennett L.
AU - Madruga-Garrido, Marcos
AU - Mingbunjerdsuk, Dararat
AU - Mir, Pablo
AU - Morer, Astrid
AU - Murphy, Tara L.
AU - Müller-Vahl, Kirsten
AU - Münchau, Alexander
AU - Nasello, Cara
AU - Oh, Dong Hun
AU - Plessen, Kerstin J.
AU - Roessner, Veit
AU - Shin, Eun-Young
AU - Song, Dong-Ho
AU - Song, Jungeun
AU - Thackray, Joshua K.
AU - Visscher, Frank
AU - Zinner, Samuel H.
AU - Bal, Vanessa H.
AU - Langley, Kate
AU - Martin, Joanna
AU - Hoekstra, Pieter J.
AU - Dietrich, Andrea
AU - Xing, Jinchuan
AU - Heiman, Gary A.
AU - Tischfield, Jay A.
AU - Fernandez, Thomas V.
AU - Owen, Michael J.
AU - O’Donovan, Michael C.
AU - Thapar, Anita
AU - State, Matthew W.
AU - Willsey, A. Jeremy
N1 - Funding Information: We wish to thank all of the families who have participated in this study, as well as all of the individuals involved in recruitment and assessment. We greatly appreciate rapid and generous access to published data from the SSC and SPARK datasets via SFARI Base ( https://base.sfari.org ); the Epi4K Consortium ( https://www.epgp.org/ ) via Daniel Lowenstein, David Goldstein, and Erin Heinzen; the Tourette International Collaborative Genetics Study (TIC Genetics, https://tic-genetics.org/ ); the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE, http://tsgenesee.mbg.duth.gr/ ); the Tourette Association of America International Consortium for Genetics (TAAICG, https://tourette.org/ ); and the Uppsala Tourette Cohort (UTC). We also thank Sarah Pyle for graphic design, Vanessa Hus Bal for expert advice, Helen R. Willsey for unwavering support and scientific feedback, and the Willsey Lab along with our extended network of colleagues for their hard work and dedication. This study was supported by grants from the National Institute of Mental Health to A.J.W. and M.W.S (R01MH115963), A.J.W. (R01NS105746), G.A.H. and J.A.T. (R01MH115958), Alyssa Rosen (R01MH115960), Donald L. Gilbert (R01MH115962), Samuel Kuperman (R01MH115961), Samuel H. Zinner (R01MH115993), Barbara J. Coffey (R01MH115959), B.W. (R25MH06048); from the Tourette Association of America to A.J.W. (Young Investigator Award); from the Human Genetics Institute of New Jersey to G.A.H. and J.A.T.; and the New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS) to G.A.H. and J.A.T. We are also grateful to the NJCTS for facilitating the inception and organization of the TIC Genetics study. This study was also supported by the Weill Institute for Neurosciences (Startup Funding to A.J.W.) and the Overlook International Foundation (to M.W.S. and A.J.W.). The ADHD study was funded by the Wellcome Trust (to A.T., M.C.O'D., and M.J.O.) and also by the MRC (A.T. and K.L.), and Action Research (A.T., M.C.O'D., and M.J.O.), with project support from Sharifah Agha, Nigel Williams, Peter Holmans, and the core lab team at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University. We also thank the Tourette Association of America International Consortium for Genetics (TAAICG) and the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE) for their ongoing collaboration and support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. Funding Information: We wish to thank all of the families who have participated in this study, as well as all of the individuals involved in recruitment and assessment. We greatly appreciate rapid and generous access to published data from the SSC and SPARK datasets via SFARI Base (https://base.sfari.org); the Epi4K Consortium (https://www.epgp.org/) via Daniel Lowenstein, David Goldstein, and Erin Heinzen; the Tourette International Collaborative Genetics Study (TIC Genetics, https://tic-genetics.org/); the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE, http://tsgenesee.mbg.duth.gr/); the Tourette Association of America International Consortium for Genetics (TAAICG, https://tourette.org/); and the Uppsala Tourette Cohort (UTC). We also thank Sarah Pyle for graphic design, Vanessa Hus Bal for expert advice, Helen R. Willsey for unwavering support and scientific feedback, and the Willsey Lab along with our extended network of colleagues for their hard work and dedication. This study was supported by grants from the National Institute of Mental Health to A.J.W. and M.W.S (R01MH115963), A.J.W. (R01NS105746), G.A.H. and J.A.T. (R01MH115958), Alyssa Rosen (R01MH115960), Donald L. Gilbert (R01MH115962), Samuel Kuperman (R01MH115961), Samuel H. Zinner (R01MH115993), Barbara J. Coffey (R01MH115959), B.W. (R25MH06048); from the Tourette Association of America to A.J.W. (Young Investigator Award); from the Human Genetics Institute of New Jersey to G.A.H. and J.A.T.; and the New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS) to G.A.H. and J.A.T. We are also grateful to the NJCTS for facilitating the inception and organization of the TIC Genetics study. This study was also supported by the Weill Institute for Neurosciences (Startup Funding to A.J.W.) and the Overlook International Foundation (to M.W.S. and A.J.W.). The ADHD study was funded by the Wellcome Trust (to A.T., M.C.O'D., and M.J.O.) and also by the MRC (A.T. and K.L.), and Action Research (A.T., M.C.O'D., and M.J.O.), with project support from Sharifah Agha, Nigel Williams, Peter Holmans, and the core lab team at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University. We also thank the Tourette Association of America International Consortium for Genetics (TAAICG) and the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE) for their ongoing collaboration and support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. Funding Information: D.L.G. has received salary/travel/honoraria from the Tourette Association of America, the Child Neurology Society, U.S. National Vaccine Injury Compensation Program, Emalex Biosciences, PTC Therapeutics, EryDel SPA, Elsevier, and Wolters Kluwer. K.M.-V. has received financial or material research support from EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), DFG: GZ MU 1527/3-1 and GZ MU 1527/3-2, BMBF: 01KG1421, National Institute of Mental Health (NIMH), Tourette Gesellschaft Deutschland e.V., Else-Kröner-Fresenius-Stiftung, GW pharmaceuticals, Almirall Hermal GmbH, Abide Therapeutics, and Therapix Biosiences. She has received consultant’s honoraria from Abide Therapeutics, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Growth, Columbia Care, CTC Communications Corp., Demecan, Ethypharm GmbH, Eurox Deutschland GmbH, Global Praxis Group Limited, Lundbeck, MCI Germany, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, and Tilray. She is an advisory/scientific board member for Alexion, CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, Ethypharm GmbH, IMC Germany, Leafly Deutschland GmbH, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, von Mende Marketing GmbH, Wayland Group, and Zambon. She has received speaker’s fees from Aphria Deutschland GmbH, Almirall, Camurus, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever Pharma GmbH, Meinhardt Congress GmbH, PR Berater, Spectrum Therapeutics GmbH, Takeda GmbH, Tilray, and Wayland Group. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer. She served as a guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects”, is an associate editor for “Cannabis and Cannabinoid Research” and an Editorial Board Member of “Medical Cannabis and Cannabinoids” und “MDPI-Reports” and a Scientific board member for “Zeitschrift für Allgemeinmedizin”. M.C.O'D. and M.J.W. received Research Grant from Takeda Pharmaceuticals out of the scope of the present work. The remaining authors declare no competing interests. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.
AB - Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.
UR - http://www.scopus.com/inward/record.url?scp=85178887598&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-43776-0
DO - https://doi.org/10.1038/s41467-023-43776-0
M3 - Article
C2 - 38057346
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8077
ER -